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Home , Hydrogen sulfide, Nitric Oxide (journal), Oxidative stress

Panthi et al. Translational (2018) 7:3 https://doi.org/10.1186/s40035-018-0108-x

REVIEW Open Access , nitric , and neurodegenerative disorders Sandesh Panthi1*, Sumeet Manandhar2 and Kripa Gautam3

Abstract

Hydrogen Sulfide (H2S) and (NO) have become recognized as important gaseous signaling with enormous pharmacological effects, therapeutic value, and central physiological roles. NO is one of the most important regulators of the pathophysiological condition in central (CNS). It is critical in the various functioning of the brain; however, beyond certain concentration/level, it is toxic. H2S was regarded as toxic with the smell like rotten egg. But, it is now regarded as emerging neuroprotectant and neuromodulator. Recently, the use of donors and inhibitors of these signaling molecules have helped us to identify their accurate and precise biological effects. The most abundant of CNS (glutamate) is the initiator of the reaction that forms NO, and H2Sishighly expressed in brain. These molecules are shedding light on the pathogenesis of various neurological disorders. This review is mainly focused on the importance of H2S and NO for normal functioning of CNS. Keywords: Hydrogen sulfide, Nitric oxide, , Gasotransmitters, Gaseous signaling molecules, Neurodegeneration, Neurodegenerative disorders

Background Nobel Prizes for Medicine/ in 1998 [7]. Because The discovery of gaseous signaling molecules like H2S, NO, of its toxic nature and noxious effects, beneficial roles of and (CO) added a new era in biomedical this were previously neglected [8]. CO was the science as these molecules have great importance in mam- second to be discovered as , and it has malian physiology [1]. They have been termed as proved its importance in cardiovascular and neuronal func- ‘gasotransmitters’ as they are either internally produced or tioning [9, 10]. However, the recognition of endogenous synthesized (endogenously) in the organism or are received level of H2S in mammalian tissue, confirmed the existence from the atmosphere and transmit chemical signals thereby of this gasotransmitters [11–13]. Synthesis, functions, and promote or induce various physiological changes inside the role of these gasotransmitters in various physiological mammalian body [2]. The term ‘gasotransmitter’ for these aspect is discussed in previous reviews [14–19]. The pri- molecules was firstly introduced in 2002, and these mary purpose of this review is to highlight the contextual molecules share some common characteristics. They are link between CNS and these gaseous signaling molecules. endogenously produced, enzymatically generated, and their production can be regulated. Gasotransmitters are perme- able to the cell membrane, but their functions inside the NO and CNS body are dependent on their concentration [3, 4]. For better NO is synthesized in CNS from an called as understating and to boost biomedical research in the field L-arginine via an called NO-synthase (NOS) in of gasotransmitters, a society named European Network on equimolar amounts with L-citrulline [20, 21]. There are Gasotransmitters was established in 2011. three different isoforms of NOS which are genetically Nitricoxidewasthefirstgaseousmoleculetobelinked different [22, 23]. Expression of NOS in various part of with its beneficial roles [5]. NO was the molecule of the the brain is shown in Table 1. Because of its ability to year in 1992 [6]injournal‘Science’ and was recognized by passively permeate cell membrane via diffusion, there is no need of receptor binding unlike conventional neuro- transmitter signaling pathways [24]. Its key potential to * Correspondence: [email protected]; [email protected] 1Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand diffuse rapidly in aqueous and environment made it Full list of author information is available at the end of the article unique from other CNS signaling molecules [25].

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Panthi et al. Translational Neurodegeneration (2018) 7:3 Page 2 of 8

Table 1 Expression of NOS in various part of brain glutamatergic neurotransmission and acts as a neuromodula- Isoforms of NOS Expression of NOS tor of excitatory neurotransmitter [28, 31]. Recent researches eNOS Vascular , Choroid plexus also demonstrated the effect of NO on inhibitory GABA- nNOS Neuronal cell bodies especially in thalamus, ergic synaptic transmission [32] via cGMP dependent olfactory bulb, claustrum, amygdala, cortex, suppression of potassium/chloride co-transporter [33]. , hypothalamus Reduction of NO may to the inability of patients to iNOS Glial cells, Macrophages, Neutrophils learn and memorize due to the impairment of long-term potentiation (LTP), as NO is responsible for the increment NO is mainly produced by Neuronal NO-synthase (nNOS) of the synaptic efficiency of pre-synaptic glutamatergic and Endothelial NO-synthase (eNOS) under normal physio- neurons and this increment induces LTP [34]. This gas- logical conditions, but Inducible NO-synthase (iNOS) is only eous signaling molecule also exerts protective role in generated after induction via inflammatory mediators like cy- brain-ischemia as a result of its strong tokines and endotoxins [26]. nNOS was the first isoform to stimulatory effect on angiogenesis and vasodilation [35]. be purified and cloned from the brain [27]. NO diffuses from Hemodynamic and vasodilation activity of NO donors [S- one neuron to another. It is not stored in any kind of synap- nitrosoglutathione (GSNO), S-nitroso-N-acetyl-penicillamine tic vesicles, and its release is independent to membrane (SNAP), sodium nitroprusside (SNP), hexam- depolarization [25, 28]. The generation of NO is similar for methylamine NONOate (MAHMA), propylamine all subtypes of NOS, but the functional regulation and level propylamine NONOate (PAPA), 3-morpholinosydnonimine of production is different. nNOS and eNOS are constitutive (SIN-1), and nitroglycerin (NTG)] has also provided cerebro- forms of NOS, and both rely on the elevation of intracellular vascular neuroprotective role in the various experimental Ca2+ level to initiate NO synthesis. nNOS requires N- model of [36, 37]. NO produced from endothelial cells methyl-D-aspartate (NMDA) receptor activation, and eNOS and adrenergic neurons regulates cerebral blood flow and needs calmodulin-dependent displacement of regulatory pro- smooth muscle tone during conditions like , hyper- teins for NO synthesis. However, iNOS activity is less sensi- capnia, , etc. eNOS mediates the basal release of tive to changes in intracellular Ca2+.But,itcanproducea NO to regulate the cerebral blood flow in various mammals. large amount of NO compared to that of NO associated with This role of NO has been confirmed by various recent eNOS and nNOS [29]. researches using NOS inhibitors [38–40]. The of NO in the target cell is associ- Age-related decrease in cGMP was also linked with in- ated with soluble Guanylate cyclase (GC)/Cyclic-guanosine creased NOS level in one recent study which may be helpful mono phosphate (cGMP) (Fig. 1) or with S-nitrosylation of for anti-aging therapies [41]. NO is also suspected to be a [30]. NO binds with the cGMP producing enzyme crucial molecule to nitrate/S-nitrosylate brain-derived called as GC and expresses its modulating effects as pre-or neurotrophic factor (BDNF) and tropomyosin-related kinase post-synaptic retrograde messenger which facilitates receptor which helps the maintenance of synaptic plasticity

Fig. 1 NO-cGMP signaling pathway: Highly membrane permeable NO binds with NO-soluble Guanylyl cyclase (sGC) which causes conformational changes, and it induces the conversion of GTP-cGMP. cGMP interacts with various intracellular like phosphodiesterase (PDE), cGMP-gated channels (CNG) and protein kinase G (PKG) which stimulates various downstream substrates. Other various pathways are triggered, and many physiological effects starts in cellular level. (Figure adapted and modified from [31]) Panthi et al. Translational Neurodegeneration (2018) 7:3 Page 3 of 8

and LTP [42]. A study has found that NO directly activates reduction of CBF after TBI [56, 57]. Various studies have ryanodine receptor (RyR), which cause the intracellular re- also proved that NO depletion has a critical role in cortical lease of Ca2+ to towards CNS, and it is believed to promote spreading depression, early brain injury, microthrombus the prolonged Ca2+ signaling in the brain. Alike, BDNF and formation, changes in blood flow after subarachnoid tropomyosin-related kinase receptor, this process is also trig- hemorrhage and if we can target this pathway, then it is gered by reversible S-nitrosylation that cause the Ca2+ re- possible to prevent secondary neuronal injury [21]. lease. This whole process is essential for cerebellar synaptic Interestingly, inhaled and intravenous (i.v.) injection of plasticity [43]. Role of NO in maintaining cerebellar synaptic sodium (NO donor) was found to have neuroprotec- plasticity, synaptic transmission efficiency, and cerebellar tive role in mice and rats during cardiac arrest (seen in the LTP are also studied and mentioned [44–46]. clinical model of ischemia/reperfusion) [58, 59]. Not only in NO was also found to have affect in the sleep-wake cycle. the mice model of ischemia, but there are also few studies Intraperitoneal (i.p.) administration of nNOS inhibitor conducted till now which support that inhaled NO or i/v caused the drop in rapid eye movement (REM) and sleep- injected of L-arginine or has protective out- wave-sleep. This relationship between the production of comes in the development of brain after injury, using various NO and sleep is also thought to be linked with various neu- experimental injury models [60–67]. This gasotransmitter is rodegenerative disorders [47]. Researchers linked the role also associated to normalize capillary blood flow, improve- of NO with experimental seizuremodelwhereoverstimula- ment of delivery of [68], prevention and reversal of tion of NMDA receptors is believed to cause the prolonged cerebral vasospasm [21, 66, 67], mitochondrial respiration release of NO [48]. However, the overactivity of same [58], development of healthy brain [21], myelination [69], NMDA receptors leading overproduction of NO may andprotectiveroleafterperipheralnerveinjury[15]. contribute to cell death-initiating various neurodegenerative However, evidence suggests that higher concentration of conditions like Alzheimer’s disease (AD), Parkinson’sdis- NO can impact neuronal death in several ways. Neuronal ease (PD), amyotrophic lateral sclerosis (ALS), stroke and death may occur due to energy depletion-induced inhibition of NOS could be neuroprotective [49]. that may stop mitochondrial respiration or slow inhibition of Brain hypoperfusion and increased vascular oxidative glycolysis. So, the role of NO is particularly dependent on its stress are the common phenomena involved in AD [50, concentration, time-course exposure, and presence/absence 51]. Few researchers also found that abnormal nNOS ex- of ROS at particular level and cells. Thus, being a neuropro- pressions are early symptoms of the AD and cognitive im- tectant at low level, NO might behave as toxicant at higher pairment involved in AD [52, 53]. It was found that concentration [70]. It was found that after the administration imbalance between the nitrotyrosine and all three isoforms of nitro-L- arginine, the infarct size of nNOS-KO mice be- of NOS results in the increased amount of nitrosylation came larger (whereas vascular NO protects after middle and oxidative products in blood and CSF of AD patients cerebral artery occlusion) and NO induced calcium release [54]. Some more physiological roles of the different isoform was found to be involved in neuronal cell death [43, 71]. Be- of NOS are listed in Table 2. causeofthisreasonNOisoftentermedasa“double-edged Stroke (ischemic stroke) is also characterized by inter- sword” [48]. One study revealed the critical role of NO dur- ruption of blood flow in the cerebral artery which ultim- ing neurodegenerative disorders and brain aging can form ately result in ischemia and tissue death. Using the blood-cerebrospinal fluid barrier and this may interfere experimental model of stroke, Huang et al. in 1996 choroid-plexus gateway activity [72]. Similarly, another find- found that eNOS deficient mice has bigger infracts than ing stated NO as the negative player in the progression of wild type [55]. eNOS was also found to maintain the level pathological nature of AD [73]. Recently, another deleterious of cerebral blood flow (CBF) after traumatic brain injury role of NOS with involvement of CNS in mouse model of (TBI). However, eNOS knock-out mice has greater dengue has been discovered [74]. NO is involved in various physiological functioning which is explained earlier in this Table 2 Physiological roles of different isoform of NOS review, however, if the physiological control of signaling Isoforms of NOS Functions pathways involved with NO or NOS fails, then NO and eNOS • Preservation and maintenance of other reactive species (RNS) can cause neuroinflam- ’ brain s microcirculation [21]. mation and neurodegeneration [75]. • Inhibition of platelet aggregation [131].

• Reduction of smooth muscle proliferation [21, 39] H2S and CNS nNOS Important roles in memory formation, CNS blood H2S is a toxic and poisonous gas having an odour of rotten flow, neuronal plasticity, transmission of pain eggs. Alike other gasotransmitters, the physiological role of signals [21]. H2S was overlooked or not paid attention due to its iNOS Response to proinflammatory or [76]. It is the most recent gaseous signaling molecule discov- endotoxins [21]. ered after NO and CO having enormous pathophysiological Panthi et al. Translational Neurodegeneration (2018) 7:3 Page 4 of 8

significance in various disease and conditions [77]. It is neuropsychiatric symptoms which cause neuronal apop- analog of , and because of its weak intermolecular force, tosis, neuronal inflammation (induced by amyloid-β), and it exists in gaseous form [78]. It is synthesized via both increased oxidative stress [90–93]. Level of H2Sinthe enzymatic and non-enzymatic pathways inside mammalian brain of patient with AD is lower than healthy people of tissue, but non-enzymatic route accounts for a small portion. same age [94]. A recent study revealed that in a rat model Cystathionine β-synthase (CBS) and Cystathionine γ-lyase of vascular dementia, plasma H2S level was lower and i.p. (CSE) are two responsible for biosynthesis of H2S injection of NaHS (H2S donor) protected neuronal injury from L-cysteine [79, 80]. 3-mercaptopyruvate sulfurtransfer- and improved behavioral (learning and memory) tests re- ase (3MST) is another enzyme that can generate H2S sults [95]. Another study demonstrated that progression through cys-catabolism pathway. CSE and CBS are localized of AD was abrupted after treatment with spa-water rich of in the cytoplasm of cell, but 3MST is expressed partly in H2Scontent[96]. Role of H2S in the improvement of cog- mitochondria and cytoplasm [81, 82]. A recent study showed nitive functioning, spatial learning and memory [96], and H2S could be produced from D-cysteine via enzyme D- neuroprotective effects [14, 90, 93, 97]isalsoprovidingus amino acid oxidase (DAO) [83, 84]. Non-enzymatically, it hopes against the AD. can be produced from thiosulfate [14]andglucose(via PD is characterized by progressive degeneration of glycolysis) or from phosphogluconate via NADPH oxidase dopaminergic neurons in the of midbrain [85, 86]. Although H2S has beneficial roles in various which is age-related and to the formation of Lewy hematologic diseases, urological disease, cardiovascular func- bodies in soma of residual neurons [77, 98]. Previous stud- tioning and oxidative stress, the effect of H2SinCNShas ies based on animal models found that inhalation or injec- attracted a lot of attention over the past few years [14, 77, tion of H2S donors prevented abnormalities related to PD 87]. Expression of different H2Sproducingenzymesin (microglial activation or motor dysfunction) including various parts of mammalian tissues is listed in Table 3 [88]. neuroprotective, neuromodulatory, and therapeutic roles Important signaling events of H2S in various neuronal cells/ of H2SinPD[99–101]. H2S-mediated anti-oxidative, anti- cell lines are listed below [89]: inflammatory, anti-apoptotic, and pro-survival effects linked with PD is also reviewed in recent paper [102]. 1. Inhibition of monoamine oxidase (via TBIisoneofthemostcommoncausesofdeathamong catecholamines) youth in today’s world and is considered as a public health 2. NMDA potentiation (via glutamate) epidemic. Memory impairment and cognitive dysfunction 3. Cystic fibrosis transmembrane conductance regulator are two immediate effects of TBI whereas rapid and ex- (CTFR) channel activation (via chloride channels) treme production of ROS are also associated with second- 4. KATP and KCa2+ channel activation (via potassium ary neuronal injury after TBI [103–106]. Karimi et al. channels) injected NaHS intraperitoneally and observed neuroprotec- 5. Intracellular calcium mobilisation, L-type and T-type tive effect of H2S in TBI induced impaired memory in rats channel activation (via calcium channels) [103]. Zhang et al. found H2S as a neuromodulator by 6. Supression of various types of neuronal toxicity (via injecting same H2S donor which decreased TBI induced le- oxidative stress) sion volume in brain [107]. NaHS proved to be the neuro- 7. Inhibition of p38-MAPK (via mitogen and protective in various other pathological conditions [108– kinase receptors) 112]. These studies are also supported by recent finding 8. Stimulation of PKA and elevation of cAMP (via PKA) which showed dynamic changes in CBS and H2S levels in various part of the brain in experimental TBI models [107]. AD, a common form of dementia, characterized by Huntington’s Disease (HD) is associated with neurotox- memory impairment, personality changes, and various icity, behavioural changes, impairment of motor coordin- ation, and oxidative stress. Paul et al. showed that there is a reduction of level of CSE in mammalian tissues with HD. Table 3 Expression of different H2S producing enzymes in various parts of mammalian tissues They demonstrated that loss of CSE mediates degeneration of neuronal cells and progression of HD [113, 114]. Studies H2S producing enzymes Expression have shown that patients with Down Syndrome (DS) has CSE Liver, Kidney, Aorta, Ileum but weakly found in brain. the higher level of CBS compared to that of a normal indi- vidual. This overexpression of CBS is believed to be the CBS Liver, Kidney, and Brain (astrocytes) cause of abnormal cognitive ability in children with DS and 3MST Liver, Kidney, Heart, Brain (Purkinje cells of cerebellum, pyramidal neurons of cerebellar may lead to AD in DS adults. Overproduction of H2Sisalso cortex, hippocampus, mitral cells of olfactory associated with ethylmalonic encephalopathy [115]. Some bulb, retinal neurons), Vascular endothelium, other neuroprotective [40, 78, 116–118], neurotransmissive Smooth muscle. role (facilitation of the induction of hippocampal LTP) Panthi et al. Translational Neurodegeneration (2018) 7:3 Page 5 of 8

[119, 120]ofH2Sanditsroleinprotectionofneuronsfrom with each other, their interactions provide beneficial ef- , degeneration [121, 122] and oxidative stress fects on mammalian physiology [14, 124, 128–130]. [121] are also studied extensively and illustrated in Table 4. Conclusions Current understandings and the published data in this field Interrelationship between NO and H S 2 has made clear about their importance in the mammalian Various studies have shown that these gasotransmitters physiology and . There are still many controver- potentiate or antagonize each other’s effect in production, sies surrounding the signaling pathways, beneficial roles, downstream of certain molecular target, and direct and harmful effects of these gasotransmitters. However, chemical interaction [123]. These gasotransmitters share their role in mediation and modulation of cell-to-cell com- the same signaling pathway in the regulation of angiogen- munication is globally accepted fact. Research and studies esis and endothelium dependent vasorelaxation [124]. Few regarding these molecule is still in the preliminary stage in articles demonstrated the common pathway of these gaso- the field of biomedical science, and especially their role in transmitters in the mammalian cardiovascular system [2, CNS is relatively unexplored. Further research also should 17, 125, 126]. Additionally, NO and CO are also found to be focused on their combinatorial effect and signaling path- have link in vasorelaxation and stimulation of calcium sen- ways regarding their antagonistic effect should be disclosed sitive potassium channels [123, 127]. for the development of new therapeutic approaches for Gasotransmitters also have a tendency to compete various neurological disorders. with each other. CO and NO have particular relation- ships with CBS. Research suggests that NO can block Abbreviations the enzymatic activity of H2S via binding with CBS and CBS: Cystathionine β-synthase; CSE: Cystathionine γ-lyase; 3MST: 3-Mercapto CBS has also high preference for CO. If eNOS is im- pyruvate sulfurtransferase; AD: Alzheimer’s disease; ALS: Amyotrophic lateral sclerosis; BDNF: Brain derived neurotrophic factor; cAMP: Cyclic peded, then it cancels out the angiogenic effects of H2S mono phosphate; CBF: Cerebral blood flow; CNS: Central nervous system; whereas blocking H2S significantly lowers the angiogenic CO: Carbon mono-oxide; CTFR: Cystic fibrosis transmembrane conductance regulator; DAO: D-amino acid oxidase; DS: Downs syndrome; effects of NO. CO and H2S act on the same molecular eNOS: Endothelial ; GC: Guanylyl cyclase; H2S: Hydrogen target but have opposite results. Even though H2S, NO, sulfide; HD: Huntington’s disease; i.p.: Intraperitoneal; i.v.: Intravenous; and CO compete and share similar signaling pathways iNOS: Inducible nitric oxide synthase; LTP: Long term potentiation; MAPK: Mitogen-activated protein kinase; NADPH: Nicotinamide adenosine dinucleotide phosphate; NMDA: N-methyl-D-aspartate; nNOS: Neuronal nitric Table 4 Physiological functions of H2S based on its oxide synthase; NO: Nitric oxide; NOS: Nitric oxide synthase; PD: Parkinson’s neuroprotective and neuromodulatory effects disease; PKA: Protein kinase A; REM: Rapid eye movement; RyR: Ryanodine Mode of physiological Evidences receptor; TBI: Traumatic brain injury functions of H2S PD: Inhibits oxygen consumption and Acknowledgements 6-hydroxydopamine evoked NADPH Not Applicable oxidation. Funding Acts on various protein kinases. Not Applicable HD: Upregulation of GSH enzyme and reveals the learning and memory Availability of data and materials problem. Not Applicable AD: Decreases protein oxidation and . Authors’ contributions Reduces -induced toxicity. SP designed and planned about the review topic. SP wrote the manuscript. SM and KG provided intellectual input to the manuscript. All authors read Influences synaptic remodelling. and approved the final manuscript. ALS: Proper regulation of GSH enzyme and reduction of oxidative stress. Ethics approval and consent to participate Not Applicable TBI: Protection via apoptotic and autophagic pathway. Consent for publication Protective effects against neuropathic Not Applicable pain and brain edema.

Neuromodulation • Long term potentiation. Competing interests − The authors declare that they have no competing interests. • CFTR Cl and KATP cycle regulation. • Enhancement of NMDA Author details receptor activity. 1Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand. 2 3 • Regulation of intracellular Ca2+. Department of Pharmacy, Chosun University, Gwangju, South Korea. China Medical University, Shenyang, People’sRepublicofChina. Panthi et al. Translational Neurodegeneration (2018) 7:3 Page 6 of 8

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